Inhibitors of histone deacetylases (HDAC) have been shown to modulate transcription and to induce cell growth arrest, differentiation and apoptosis. HDAC inhibitors also enhance the cytotoxic effects of therapeutic agents used in cancer treatment, including radiation and chemotherapeutic drugs. Marks, P., Rifkind, R. A., Richon, V. M., Breslow, R., Miller, T., Kelly, W. K. Histone deacetylases and cancer: causes and therapies. Nat Rev Cancer, 1, 194-202, (2001); and Marks, P. A., Richon, V. M., Miller, T., Kelly, W. K. Histone deacetylase inhibitors. Adv Cancer Res, 91, 137-168, (2004). Moreover, recent evidence indicates that transcriptional dysregulation may contribute to the molecular pathogenesis of certain neurodegenerative disorders, such as Huntington's disease, spinal muscular atrophy, amyotropic lateral sclerosis, and ischemia. Langley, B., Gensert, J. M., Beal, M. F., Ratan, R. R. Remodeling chromatin and stress resistance in the central nervous system: histone deacetylase inhibitors as novel and broadly effective neuroprotective agents. Curr Drug Targets CNS Neurol Disord, 4, 41-50, (2005). For example, suberoylanilide hydroxamic acid (SAHA) has been shown to penetrate into the brain, and to improve dramatically the motor impairment in a mouse model of Huntington's disease, thus validating the pursuit of this class of molecules in the treatment of neurodegenerative diseases. Hockly, E., Richon, V. M., Woodman, B., Smith, D. L., Zhou, X., Rosa, E., Sathasivam, K., Ghazi-Noori, S., Mahal, A., Lowden, P. A., Steffan, J. S., Marsh, J. L., Thompson, L. M., Lewis, C. M., Marks, P. A., Bates, G. P. Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, ameliorates motor deficits in a mouse model of Huntington's disease. Proc Natl Acad Sci USA, 100, 2041-2046, (2003). A recent review has summarized the evidence that aberrant histone acetyltransferase (HAT) and histone deacetylases (HDAC) activity may represent a common underlying mechanism contributing to neurodegeneration. Moreover, using a mouse model of depression, Nestler has recently highlighted the therapeutic potential of histone deacetylation inhibitors (HDAC5) in depression. Tsankova, N. M., Berton, O., Renthal, W., Kumar, A., Neve, R. L., Nestler, E. J. Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action. Nat Neurosci, 9, 519-525, (2006).
Thus, the potential of HDAC inhibitors is tremendous, but the translation of these ideas to the clinic will likely require the design of isoform selective molecules to minimize side effect issues. While several HDAC inhibitors are now in the clinic, most of these do not show significant selectivity for the individual HDAC isoforms, of which eleven are currently known that operate by zinc dependent mechanisms (class I includes HDACS 1, 2, 3, 8, and 11) and class II includes 4, 5, 6, 7, 9, and 10). Hu, E., Dul, E., Sung, C. M., Chen, Z., Kirkpatrick, R., Zhang, G. F., Johanson, K., Liu, R., Lago, A., Hofmann, G., Macarron, R., de los Frailes, M., Perez, P., Krawiec, J., Winkler, J., Jaye, M. Identification of novel isoform-selective inhibitors within class I histone deacetylases. J Pharmacol Exp Ther, 307, 720-728, (2003). Recently, it has been suggested that the non-sirtuin HDACs can be divided into three equally distinct groups with the third class comprised of proteins related to the human HDAC11 gene. Gregoretti, I. V., Lee, Y. M., Goodson, H. V. Molecular evolution of the histone deacetylase family: functional implications of phylogenetic analysis. J Mol Biol, 338, 17-31, (2004).
Class I enzymes (HDACs 1, 2, 3 and 8) range in size from 42-55 kDa, and are homologs of yeast Rpd3. They are ubiquitously expressed, predominantly nuclear and mainly function as transcriptional corepressors. Class II enzymes (HDACs 4, 5, 6, 7, 9 and 10) range in size from 120-160 kDa are homologs of yeast Hda1. Their distribution is tissue specific, suggesting distinct functions in cellular differentiation and developmental processes. Finally, as mentioned above, HDAC 11 is another recently identified member of the HDAC family that bears low similarities with HDAC class I and class II and therefore could not be definitively classified in either class.
In order to learn more about the role that the individual HDACs play in cell growth and/or differentiation, neuroprotection, and apoptosis, it is important to develop agents showing selectivity for individual isoforms or a small subset of these isoforms. While some degree of isoform selectivity has been shown by a few compounds, this problem of identifying selective inhibitors is far from solved, and the problem is complicated by the interactions of the HDACs with each other as well as other proteins (cofactors) that can possibly alter their interaction with various inhibitors. Glaser, K. B., Li, J., Pease, L. J., Staver, M. J., Marcotte, P. A., Guo, J., Frey, R. R., Garland, R. B., Heyman, H. R., Wada, C. K., Vasudevan, A., Michaelides, M. R., Davidson, S. K., Curtin, M. L. Differential protein acetylation induced by novel histone deacetylase inhibitors. Biochem Biophys Res Commun, 325, 683-690, (2004). However, experimental evidence shows that the different HDACs may have intrinsic differences in substrate specificity. Hildmann, C., Wegener, D., Riester, D., Hempel, R., Schober, A., Merana, J., Giurato, L., Guccione, S., Nielsen, T. K., Ficner, R., Schwienhorst, A. Substrate and inhibitor specificity of class 1 and class 2 histone deacetylases. J Biotechnol, 124, 258-70, (2006).
In addition to the need for HDAC inhibitors in the treatment of cancer and neurological disorders (see for example US Patent Applications 2005/0014839 and 2005/0032831; both of which are hereby incorporated by reference) there is a significant need in the art for novel compounds which show HDAC isoform selectivity.